The citation of references herein shall not be construed as an admission that such is prior art to the present invention.
CD8+ CTL play an essential role in killing of virus-infected and transformed cells but in unmanipulated hosts fail to control tumor growth. Although the frequency of antigen-specific T cells in cancer patients is low, demonstrable priming occurs in response to tumor growth [1]. Investigation of animal models and tumor-bearing patients show production of antigen-specific CTL in the periphery but whose effector phase T cell function is suppressed upon entrance into the tumor [2,3], a phenotype postulated to contribute to tumor escape from immune-mediated eradication [4]. This implies the tumor microenvironment induces tumor infiltrating T cell (TIL) lytic dysfunction, a conclusion that has been substantiated by several experimental approaches [5]. In a murine model of colorectal carcinoma (MCA38) nonlytic TIL were shown to be recently-activated effector memory cells (CD44+ CD62LloCD69+CD95L+CD122+CD127+ [6]). The dysfunctional lytic phenotype was subsequently shown to be due to a tumor-induced block in proximal TCR-mediated signaling that obviates ZAP70 activation, in turn due to rapid inactivation of p56lck upon contact with cognate tumor cells [7]. The nature of the tumor-induced block remained undefined in advance of the discoveries presented herein.